The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (RTKs) has long been recognized as including important oncology targets. ErbB3, an EGFR family member, been recently recognized as an important player in solid tumor biology and has emerged as a key unaddressed target in oncology. EGFR (also designated ErbB1) and ErbB2, two related members of the family, are known to drive progression of a significant subset of human tumors when inappropriately activated. Antibody-based inhibitors (Erbitux®, Vectibix®, and Herceptin®) and small molecule tyrosine kinase inhibitors (Iressa®, Tarceva®, and Tykerb®) that target EGFR and ErbB2 have been approved by the FDA for the treatment of a variety of cancers including mammary carcinoma, lung cancers, colon cancer among other oncological indications.
Unlike the three other members of the EGFR family of RTKs, data indicate that ErbB3 is a pseudo kinase that functions as an obligate heterodimer with other ErbB receptors. ErbB3-related signaling has been identified as an important driver of tumor cell survival and growth as well as poor patient prognosis. In addition, signaling involving ErbB3 is utilized by a subset of tumors as an escape mechanism from therapies that target other ErbB receptors.
In tumors, ErbB3 is activated in one of three known manners. First, the Neuregulin 1 (Nrg1) and Neuregulin 2 (Nrg2) family of ligands stabilize a heterodimerization-competent conformation of ErbB3 that allows the receptor to signal by partnering either with ErbB2, or the ligand stimulated activated forms of EGFR or ErbB4. This requirement for ligand stimulation, however, can be bypassed in cases where ErbB2 is very highly overexpressed (such as in ˜20% of breast and gastric cancers). Through mass-action, ErbB2 can force heterodimerization with ErbB3 in a ligand-independent manner to provide survival cues to tumor cells. Lastly, oncogenic mutations in ErbB3, which presumably relieve auto-inhibitory mechanisms, can result in increased basal receptor activity when its co-receptors are present. From a therapeutic perspective, a drug that targets ErbB3 would ideally interfere with all mechanisms of ErbB3 activation relevant in disease.
There is a need for therapies modulating ErbB3 to manage, treat or ameliorate conditions involving ErbB3 and/or abnormal ErbB3 signaling or abnormal ErbB3 expression.